Microglial Inflammatory Signaling Orchestrates the Hypothalamic Immune Response to Dietary Excess and Mediates Obesity Susceptibility

Valdearcos, Martín; Douglass, John D.; Robblee, Megan M.; Dorfman, Mauricio D.; Stifler, Daniel R.; Bennett, Mariko L.; Gerritse, Irene; Fasnacht, Rachael; Barres, Ben A.; Thaler, Joshua P.; Koliwad, Suneil K.

doi:10.1016/j.cmet.2017.05.015

Cited by 337 publications

(345 citation statements)

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“…; Valdearcos et al . , ; Dorfman and Thaler ). On the other hand, here it is found that in the male Sim1‐Cre:Rosa‐mEGFP mice exposed to the palm oil‐based HF diet, neuronal damage in the PVN is not paralleled by reactive microgliosis (Fig.…”

Section: Resultsmentioning

confidence: 97%

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Injury to hypothalamic Sim1 neurons is a common feature of obesity by exposure to high‐fat diet in male and female mice

Nyamugenda

Trentzsch

Russell

et al. 2019

Journal of Neurochemistry

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The hypothalamus is essential for regulation of energy homeostasis and metabolism. Feeding hypercaloric, high‐fat (HF) diet induces hypothalamic arcuate nucleus injury and alters metabolism more severely in male than in female mice. The site(s) and extent of hypothalamic injury in male and female mice are not completely understood. In the paraventricular nucleus (PVN) of the hypothalamus, single‐minded family basic helix‐loop helix transcription factor 1 (Sim1) neurons are essential to control energy homeostasis. We tested the hypothesis that exposure to HF diet induces injury to Sim1 neurons in the PVN of male and female mice. Mice expressing membrane‐bound enhanced green fluorescent protein (mEGFP) in Sim1 neurons (Sim1‐Cre:Rosa‐mEGFP mice) were generated to visualize the effects of exposure to HF diet on these neurons. Male and female Sim1‐Cre:Rosa‐mEGFP mice exposed to HF diet had increased weight, hyperleptinemia, and developed hepatosteatosis. In male and female mice exposed to HF diet, expression of mEGFP was reduced by > 40% in Sim1 neurons of the PVN, an effect paralleled by cell apoptosis and neuronal loss, but not by microgliosis. In the arcuate nucleus of the Sim1‐Cre:Rosa‐mEGFP male mice, there was decreased alpha‐melanocyte‐stimulating hormone in proopiomelanocortin neurons projecting to the PVN, with increased cell apoptosis, neuronal loss, and microgliosis. These defects were undetectable in the arcuate nucleus of female mice exposed to the HF diet. Thus, injury to Sim1 neurons of the PVN is a shared feature of exposure to HF diet in mice of both sexes, while injury to proopiomelanocortin neurons in arcuate nucleus is specific to male mice. Open Science Badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

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Section: Resultsmentioning

confidence: 97%

“…; Valdearcos et al . , ; Dorfman and Thaler ). Moreover, in male rodents, exposure to HF diet induces impaired post‐translational processing of POMC to generate α‐MSH, loss of POMC neuron synapses, and impaired secretion of α‐MSH (Levin ; Enriori et al .…”

Section: Discussionmentioning

confidence: 97%

Injury to hypothalamic Sim1 neurons is a common feature of obesity by exposure to high‐fat diet in male and female mice

Nyamugenda

Trentzsch

Russell

et al. 2019

Journal of Neurochemistry

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“…Nonetheless, MBH gliosis might be an early finding in children that predisposes them to future insulin resistance indirectly via an effect favouring visceral fat deposition. In rodent models of diet‐induced obesity (DIO), inflammatory responses from glial cells, including astrocytes and microglia, have been shown to be necessary for the hyperphagia and weight gain seen during high fat feeding, but discerning if MBH gliosis is a marker or pathogenic component of obesity and insulin resistance in humans will require additional and longitudinal data, as the current cross‐sectional design limits such interpretations. In addition, dietary factors related to MBH gliosis in humans have yet to be defined and are important area for future research.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, dietary factors related to MBH gliosis in humans have yet to be defined and are important area for future research. Studies with rodent models have commonly implicated the HFD, but sucrose ingestion and neonatal overnutrition could also contribute to the inflammatory process and altered glucose metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…Rodent studies implicate hypothalamic inflammation in the pathophysiology of obesity . Dietary excess due to consumption of high‐fat diet (HFD) triggers an inflammatory response in the mediobasal hypothalamus (MBH), even before weight gain begins and affects the function and number of key neurons involved in energy balance, ie, proopiomelanocortic (POMC) cells.…”

Section: Introductionmentioning

confidence: 99%

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Initial evidence for hypothalamic gliosis in children with obesity by quantitative T2 MRI and implications for blood oxygen‐level dependent response to glucose ingestion

et al. 2018

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Summary Objective In adults, hypothalamic gliosis has been documented using quantitative T2 neuroimaging, whereas functional magnetic resonance imaging (fMRI) has shown a defective hypothalamic response to nutrients. No studies have yet evaluated these hypothalamic abnormalities in children with obesity. Methods Children with obesity and lean controls underwent quantitative MRI measuring T2 relaxation time, along with continuous hypothalamic fMRI acquisition to evaluate early response to glucose ingestion. Results Children with obesity (N = 11) had longer T2 relaxation times, consistent with gliosis, in the mediobasal hypothalamus (MBH) compared to controls (N = 9; P = 0.004). Moreover, there was a highly significant group*region interaction (P = 0.002), demonstrating that signs of gliosis were specific to MBH and not to reference regions. Longer T2 relaxation times correlated with measures of higher adiposity, including visceral fat percentage (P = 0.01). Mean glucose‐induced hypothalamic blood oxygen‐level dependent signal change did not differ between groups (P = 0.11). However, mean left MBH T2 relaxation time negatively correlated with glucose‐induced hypothalamic signal change (P < 0.05). Conclusion Imaging signs of hypothalamic gliosis were present in children with obesity and positively associated with more severe adiposity. Children with the strongest evidence for gliosis showed the least activation after glucose ingestion. These initial findings suggest that the hypothalamus is both structurally and functionally affected in childhood obesity.

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The involvement of 4‐1BB/4‐1BBL signaling in glial cell‐mediated hypothalamic inflammation in obesity

et al. 2018

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Obesity‐induced inflammation occurs not only in peripheral tissues but also in areas of the central nervous system. Glial cells such as astrocytes and microglia play crucial roles in obesity‐related hypothalamic inflammation, leading to the derangement of energy metabolism and neurodegenerative pathologies. Here, we show that the interaction of 4‐1 BB /4‐1 BBL between lipid‐laden astrocytes/microglia promotes hypothalamic inflammation in obesity. Stimulation of 4‐1 BB , a member of the TNF receptor superfamily, and/or its ligand 4‐1 BBL on astrocytes and/or microglia with a specific agonist resulted in activation of the inflammatory signaling pathway and enhanced production of inflammatory mediators. Contact coculture of lipid‐laden astrocytes and microglia increased the production of inflammatory mediators, and blockade of the 4‐1 BB /4‐1 BBL interaction reduced the inflammatory response. Moreover, deficiency of 4‐1 BB reduced hypothalamic inflammation in obese mice fed an high‐fat diet. These findings suggest that 4‐1 BBL /4‐1 BB signaling enhances the glial cell‐mediated inflammatory cross talk and participates in obesity‐induced hypothalamic inflammation.

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Microglial Inflammatory Signaling Orchestrates the Hypothalamic Immune Response to Dietary Excess and Mediates Obesity Susceptibility

Cited by 337 publications

References 58 publications

Injury to hypothalamic Sim1 neurons is a common feature of obesity by exposure to high‐fat diet in male and female mice

Injury to hypothalamic Sim1 neurons is a common feature of obesity by exposure to high‐fat diet in male and female mice

Initial evidence for hypothalamic gliosis in children with obesity by quantitative T2 MRI and implications for blood oxygen‐level dependent response to glucose ingestion

The involvement of 4‐1BB/4‐1BBL signaling in glial cell‐mediated hypothalamic inflammation in obesity

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